Drug Abuse

Drug Abuse

• Drug abuse is the use of a substance for a purpose that is not consistent with legal or medical guidelines.
• Drug abuse is used for euphoric feelings.
• Drug misuse is the use of a substance for a purpose that is not consistent with legal medical guidelines, mostly prescription drugs.
• Misuse is mostly related to taking the drug for a faster or better effect, as opposed to using it for its intended purpose
• Psychoactive drugs can be CNS depressants, CNS stimulants, and/or hallucinogens.

Tolerance

• Tolerance is the decreased effect of a drug that develops with continued use.
• Acquired tolerance results from repeated drug administration that shifts the dose-response curve to the right. A larger dose is needed to achieve the same effect as before.
• Innate tolerance refers to pre-existing interindividual variations in sensitivity to a drug. Individual variations in sensitivity occur before the first administration of a drug.
• Acquired tolerance includes pharmacokinetic, pharmacodynamic, and learned components.
• Pharmacokinetic tolerance develops when the body's capacity to metabolize or excrete the drug increases.
• Pharmacodynamic tolerance is caused by neuronal adaptations.
• Short-term drug exposure can alter neurotransmitter release, receptor numbers, ion channel conductance, or signal transduction.
• Longer-term use causes changes in gene expression, related to adaptations of learning and memory.

Alcohol

• Alcohol modulates the central nervous system's major inhibitory and excitatory neurotransmitter systems.
• Alcohol increases chloride conductance through GABA receptors, resulting in cellular hyperpolarization.
• Alcohol decreases calcium conductance through NMDA receptors.

Molecular Adaptations to Chronic Alcohol Exposure

• Internalization and decreased surface expression of "normal" a1 subunit-containing GABA receptors, increased expression of "low alcohol sensitivity" a4 subunit-containing GABA receptors, and increased phosphorylation of NMDA receptors containing "high conductance" NR2B subunits, are all molecular adaptations to chronic alcohol exposure.
• Thus, neuroadaptation results in tolerance to the acute depressant effects of alcohol and occurs concomitantly with dependence.
• During withdrawal, these adaptations result in generalized hyperexcitability of neurons. This results in anxiety, insomnia, delirium, and potentially seizures.

Cocaine

• Acute cocaine exposure inhibits dopamine reuptake transporters (DAT), which leads to an increase in synaptic dopamine. This activation leads to increased activity, and euphoria.
• Increased extrasynaptic dopamine also activates D2 autoreceptors which, in turn, leads to decreased dopamine synthesis.
• During withdrawal, the decreased synaptic dopamine levels and increased clearance through DAT cause activation of postsynaptic dopamine receptors. Feelings of dysphoria, fatigue, and anhedonia result.

Dependence

• The dependence can be physical and psychological.
• Physical dependence is characterized by withdrawal symptoms upon discontinuation of the drug.
• New terminology for physical dependence is dependence.
• Psychological dependence is characterized by craving for the drug, even after acute withdrawal symptoms subside.
• The individual is prone to relapse.
• New terminology for psychological dependence is addiction.

Addiction

• Addiction refers to substance dependence.
• Drug-seeking behavior is fundamental to this.
• Addiction is described as "rewiring" of the brain due to persistent adaptations to drug use.
• Cravings and relapses can occur long after cessation.

Dependence

• The medial forebrain bundle and ventral tegmental area (VTA) are termed "pleasure centers" or reward areas.
• A subset of dopaminergic neurons from the VTA project to the nucleus accumbens (NAc).
• These neurons are crucial for the brain reward pathway and behavior reinforcement.

Variables Affecting the Development of Substance Use Disorders

• The development of substance use disorders depends on: the nature of the drug, genetic factors, acquired psychological factors, social traits of the drug user, and environmental factors.
• The ability of a drug to activate reward mechanisms is strongly correlated to its ability to cause addiction.
• Pharmacokinetic properties of the drug influence its effects on the brain. The faster the drug is absorbed into the body and reaches target neurons, the greater the activation of reward pathways.
• Rapid elimination is more likely to lead to addiction than drugs with slower elimination.
• This is due to the maintenance of drug concentration at target sites for a longer duration, thus diminishing the severity of withdrawal symptoms.

Drug misuse and abuse

• Drug misuse is the use of a substance for a purpose not consistent with its legal or medical guidelines.
• examples: taking over-the-counter medications for unapproved purposes of duration and dose for faster medical effect or to feel better.
• Drug abuse: using a substance to elicit or enhance feelings, like certain sensations or to increase excitement.

Drugs of Abuse

• All of the substances listed are described as drugs of abuse because they are used in ways that have not been medically approved
• Addictive drugs usually activate the mesolimbic dopamine reward pathway.

Agents that Can Cause Dependence

• These can be CNS depressants or CNS stimulants.

Psychostimulants

• Psychostimulants are psychotropic substances stimulating the central nervous system.
• They cause excitation, elevated mood, increased alertness, and arousal.
• Examples include amphetamines, cocaine, caffeine, nicotine

Methylxanthines

• Methylxanthines, including caffeine, theophylline, and theobromine, are CNS stimulants.
• Found in coffee, tea, soda, chocolate etc.
• They have alerting effects, improve performance, and can cause insomnia.
• Adenosine is blocked by these substances, leading to dopamine and norepinephrine release in the brain.

CNS Depressants

• This class includes barbiturates, benzodiazepines, ethanol, methanol, inhalants, and opioids.
• Sedative and hypnotic properties are often described for these substances.
• They also have anxiolytic effects to reduce tension.
• Use for these purposes can be inappropriate.

Benzodiazepines and Barbiturates

• These are sedative/hypnotic agents widely used for anxiety and insomnia.
• Euphoria can be associated with use during intoxication.
• Anxiolytic and tension-reducing properties may enhance the reinforcing effects and abuse potential of these drugs.
• They increase the efficiency of GABAergic pathways, but chronic use can induce down-regulation of these pathways via neuroadaptation.

Alcohol

• Depression of inhibitory control leads to euphoria and CNS stimulation as early effects of alcohol.
• Higher blood alcohol levels result in impaired motor coordination, emotional control, and judgment.
• Overdose can lead to respiratory depression, and withdrawal can be life-threatening.
• Ethanol affects GABA receptors, NMDA glutamate receptors, and cannabinoid receptors.

Opiates

• Opiates are CNS depressants derived from the poppy plant.
• Common opiates include opium, heroin, morphine, and codeine.

Opioids

• Addicts describe an intense euphoric feeling (rush) associated with the intravenous injection of heroin.
• Sites of action of these opioids in the brain reward system are in the ventral tegmental area, where GABAergic interneurons tonically inhibit the dopaminergic neurons involved in the reward pathway in the nucleus accumbens.
• Administration of exogenous opioids decreases GABA release and increases dopamine release, resulting in a strong reward response in the nucleus accumbens.

Treatment of Addiction

• Pharmacological treatment: Detoxification is the first step.
• The goal is to allow the body to adapt to the absence of the drug/alcohol, and prepare the patient for long-term rehabilitation.
• Chronic treatment strategies involve administration of an agent generating aversive effects.
• Example: disulfiram inhibits aldehyde dehydrogenase, leading to acetaldehyde accumulation and aversive symptoms like facial flushing, headache, nausea.
• Another strategy is opioid antagonists like naltrexone, to block the effects of the drug on opioid receptors, thus preventing the high.
• Psychosocial treatment: includes cognitive behavioral therapy and self-help programs like Alcoholics Anonymous. Integration of pharmacological and psychosocial approaches often results in a better outcome.